Parkinson's disease is characterized by a progressive degeneration of dopaminergic neurons of the nigrostriatal pathway. Current treatments for Parkinson's disease are dependent upon dopamine replacement therapy. After long-term dopamine replacement therapy, patients experience a "wearing-off" and "on-off" response fluctuation to the therapy. An alternative approach to treating Parkinson's disease would be to target non-dopaminergic receptors and identify selective compounds either as monotherapies or as adjuncts with L-DOPA or other dopamine agonists. Adenosine modulates basal ganglia neurotransmission by an adenosine A2A receptor-mediated mechanism. This Phase I proposal focuses on a new systematic discovery approach using combined in silico and in vitro screening. We believe this approach is useful and is likely to be successful in finding lead compounds with potent and highly selective activities at adenosine receptor A2A, A2A-D1 or A2A-D2 receptor or receptors. These lead compounds will then be further developed into drugs useful in treating Parkinson's disease.